Sensor-catheters used as an indwelling catheter can be used to monitor physiological values such as pressure, oxygen, pH etc., over some period of time. During a long contact-time, the blood can clot on the surfaces of the sensor-catheter. This clotting is caused by the cascadic biochemical mechanism of the blood, forming a deposit called thrombus. This generation of thrombi can be initiated by the bio-incompatibility of a foreign surface because of the chemical, physical and mechanical properties of the surface. The formation of thrombi is not only caused by properties of the foreign surface but also by a collision of a blood platelet with the foreign surface irritating the biochemical behavior of that platelet which can result in the formation of a thrombus in a remote part of the blood circulation system. It is important to control this biochemical reaction to avoid thrombogeneration which can lead to embolism or can at least impair the functionality of the sensor-catheter. In many cases the monitoring with a sensor-catheter will be done during a short time, e.g., during catheterization for diagnostical purposes. In those cases the thrombogenic processes can be controlled by the administration of anti-coagulantia, of which heparin is the most widely used. However, heparin administration during a longer period of time can lead to adverse effects, e.g. to osteoporosis (softening of the bone tissue) and to the so-called "heparin rebound effect" in which heparin activity returns somewhere in the bloodstream some hours after its neutralization. During monitoring in the vascular system of the newborn baby, the heparin can initiate further problems in the instable metabolism of the baby.
As is known from a reviewing article ("Heparinised polymers as thromboresistant biomaterials" published by J. E. Wilson in Polym. plat. Technol. Eng(16(2) 119-208 (1981)), several trials have been made to bind heparin to the surfaces of medical devices which shall be introduced into the bloodstream. In the literature there is still a controversial dispute about the activity and the antithrombogenic mechanism of heparin.
According to the review by J. E. Wilson (see above), the anti-thrombogenity may be caused by the leaching of heparin from the polymer. The microatmosphere of the dissolved heparin around the device causes the anti-thrombogenity.
The covalent binding of heparin to a polymer results in a decrease of its activity. However, M.F.A. Goosen and M. V. Sefton ("Properties of a heparin-poly(vinylalcohol)-hydrogel coating" published in the Journal of Biomed. Mat. Res., Vol. 17, 359-373 (1983)), showed that chemical binding of heparin to polyvinyl alcohol positively affects the anti-thrombogenity of the polymer. The could prove that no heparin leached out from the P.V.A. hydrogel during their biological activity measurements.
Subject matter of the European Patent 0 149 693 is a method of forming on medical devices an anti-thrombogenic layer comprising a hydrogel forming polymer, e.g. polyvinyl alcohol, and heparin, which is characterized by the steps of a) preparing an aqueous solution of photosensitive hydrogel forming polymer such as polyvinyl alcohol or polyvinylpyrrolidone, a cross-linking agent, and heparin; b) coating the medical device with said solution; and c) exposing the coated device to ultraviolet radiation.
This new method is easy to perform and relies on the well-known principles of lithography and allows for the manufacture of antithrombogenic layers on semiconductor or electrically conducting surfaces specifically usable for the manufacture of sensors, catheters or other medical instruments.
It is further known from an article by T. Tsunoda and Y. Yamaoka (J. of Applied Polymer Science, Vol. 8 (1964), pp. 1379-1390) that polyvinyl alcohol can be crosslinked by light-sensitive tetrazonium salts.
It has now surprisingly been found that by far better results than those described in the above European Patent 0 149 693 can be obtained not only during the formation of anti-thrombogenic layers but of layers comprising a biochemically active material on a substrate surface in case this layer is deposited using a specific combination of crosslinking agents, i.e. a polyazonium compound in combination with glutardialdehyde.